IL46484A

IL46484A - 2-hydroxy-10-(3-(4-(2-hydroxyethyl)-piperidino)propyl)-phenothiazine derivatives processes for the preparation thereof and pharmaceutical compositions containing the same

Info

Publication number: IL46484A
Application number: IL7546484A
Authority: IL
Original assignee: Rhone Poulenc Ind
Priority date: 1974-01-22
Filing date: 1975-01-21
Publication date: 1977-11-30
Also published as: CS187458B2; IE40364B1; AU7748775A; AT338816B; SE7500642L; SU577994A3; DE2502504A1; NL165739C; SE414029B; ES439072A1; NL165739B; DK17275A; AU470810B2; CH602718A5; FI57948C; DE2502504B2; LU71688A1; AR205635A1; JPS50123682A; HU168855B

Description

New 2-hydroxy-10-{3- [4- (2-hydroxyethyl) -piperidino] propyl}-phenothiazine derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same ϊπικ m an mrr n Jiunyni jnasn? THIS INVENTION relates to new derivatives of phenothiazine.

During the past thirty years considerable research and experimentation have been conducted in the field of IS-substitu ed phenothiazine derivatives and certain of these compounds have been found to possess valuable therapeutic properties. Some are useful primarily on account of outstanding antihistaminic activity, others because of their tranquillising action and of their efficacy as anti-shock agents and yet others are, for example, effective agents for controlling or minimising motion-sickness. It has nevertheless been demonstrated that of the very large number of possible N-substituted phenothiazine compounds that have been proposed or tested by various workers, only comparatively few types have useful application in human or veterinary medicine and that both the nature and the degree of useful effect can radically alter even with apparently small changes in chemical structure.

It is an object of the present invention to provide new phenothiazine derivatives v/hich possess unexpectedly useful pharmacological properties of a nature hereinafter referred to in detail and of a degree of activity that could not have been predicted from knowledge of their chemical structure.

The phenothiazine derivatives of the present invention are those which conform to the general formula: wherein X represents a methylthio, methylsulphonyl or dimethylsulphamoyl radical, R represents a hydrogen atom or an alkyl radical containing 1 to 10 carbon atoms, a phenylalkyl radical containing 1 to 4 carbon atoms in the alkyl part (preferably benzyl) , or a tetrahydropyranyl radical, A represents -(CH2>3- or -CH2-CH(CH3)-CH2- (preferably -(CH2 3-^, and ^ represents a hydrogen atom or an alkanoyl radical containing 1 to 16 carbon atoms in the alkyl part or an alkenoyl radical containing 2 to 16 carbon atoms in the alkenyl part, and acid addition salts thereof. The numbering of the positions of the pheno-thiazine ring is in accordance with Beilstein.

In Israel Patent 29707 (corresponding to French Pat. 1,558,912 and S. African Pat. 68/1990 whose abstract o appears in CA 70 , 106542p) there are described phenthiazine ester derivatives having superior properties to the phenthiazine derivatives described in Israel Patent 14 909 (which corresponds to Brit. Pat. 904,208). These esters which show an activity of the same type as that of the alcohols from which they are derived, but with a longer duration of action, nevertheless possess some anti-emetic properties associated with secondary side effects which could prove to be undesirable.

In contradistinction to said prior art esters the compounds of the present invention possess powerful anti-emetic characteristics devoid of secondary side effects and are further structurally distinguished by the presence of the RO-substituent in the 2-position.

Similarly the products described in British Patent 872 202 differ from those of the present invention in their spectrum of activity and in the absence of the teaching or suggestion of an RO substituent in said 2-position.

According to a feature of the present invention, the phenothiazine derivatives of general formula I, wherein R represents an alkyl radical containing 1 to 10 carbon atoms, a phenylalkyl radical containing 1 to 4 carbon atoms in the alkyl part, or a tetrahydro-pyranyl radical, R represents a hydrogen atom and the 1 symbols X and A are as hereinbefore defined, are pared by the process which comprises reacting a phenothiazine derivative of the general formula: A-Y - 2a - [wherein X and A are as hereinbefore defined, represents an alkyl radical containing 1 to 10 carbon atoms, a phenylalkyl radical containing 1 to 4 carbon atoms in the alkyl part, or a tetrahydropyranyl radical, and Y represents the acid residue of a reactive ester such as a halogen (preferably chlorine) atom or a sulphuric or sulphonic acid ester radical, e.g. the methanesulphonyloxy or toluene-pj-sulphonyloxy group] with 4-( 2-hydroxyethyl )piperidine. The reaction is generally carried out in an organic solvent, e.g. dimethylformamide, in the presence of an alkaline condensation agent, e.g. sodium bicarbonate, and at a temperature between 50°C. and the boiling point of the reaction mixture.

The phenothiazine derivatives of general formula II can be prepared by the reaction of a compound of the general formula: Y^ - A - Y III (wherein A is as hereinbefore defined, and the symbols Y and Y^, which are preferably different, each represent a halogen atom or a sulphuric or sulphonic acid ester radical) with a compound of the general formula: H wherein X and I¾2 are as hereinbefore defined. The reaction is generally carried out in an organic solvent such as a ketone, e.g. methyl ethyl ketone, in the pr senc of an alkaline condensation agent, e.g. potassium hydroxid The compounds of general formula IV wherein X represents a metliylthio or dimethylsulphamoyl radical can be prepared by etherification of a phenothiazine of the general formula: H wherein represents a methylthio or dimethylsulphamoyl radical, by means of an alkylating agent such as a dialkyl sulphate or an alkyl or phenylalkyl halide when ί¾2 in formula IV represents an alkyl or phenylalkyl radical or by means of dihydropyran when represents a tetrahydro-pyranyl radical. Etherification using a dialkyl sulphate or an alkyl or phenylalkyl halide is generally effected in an organic solvent such as a ketone, e.g. methyl ethyl ketone, in the presence of an alkaline condensation agent such as an alkali metal carbonate, e.g. sodium carbonate. 3tlierification using dihydropyran is generally effected in an anhydrous acid medium, such as a solution of hydrogen chloride in ethanol or in methanol, in the presence of an excess of dihydropyran.

BIG compounds of general formula V can be prepared by the reduction of a phenothiazinone of the general formulas wherein is as hereinbefore defined. The reduction is generally effected by means of sodium hydrosulphite in an organic or aqueous-organic solvent. Alcohols such as ethanol or ketones such as methyl ethyl ketone can be used as organic solvents.

The phenothiazinone of general formula VI wherein X^ represents the dimethylsulphamoyl radical can be prepared by oxidation of 3-dimethylsulphamoyl-phenothiazine. Ferric chloride in an aqueous medium at a temperature of about 20°C is generally used as the oxidising agent.

'He phenothiazinone of the general formula VI wherein X represents the methylthio radical can be prepared by the reaction of the zinc salt of 2-amino- -methylthio-thxophenol with 2-chlorohydroquinone in the presence of oxygen, T e compounds of general formula IV wherein X represents a methylsulphonyl radical can be prepared from compounds of general formula IV wherein X represents the methylthio radical by carrying out sequentially the following reactions: IX wherein is as hereinbefore defined.

The acetylation of the phenothiazines of formula VII can be effected by means of acetic anhydride.

The oxidation of the phenothiazines of formula VIII to yield phenothiazines of formula IX can be effected in accordance with the usual methods for oxidising a methylthio radical to a methylsulphonyl radical. Hydrogen peroxide in a basic medium is preferably used.

The reduction of the phenothiazines of formula IX to yield the phenothiazines of formula X can be effected in accordance with lcnown methods which make it possible to reduce a sulphoxide and to remove an acetyl radical without affecting the rest of the molecule. Zinc in the presence of acetic acid, optionally in an organic solvent such as dimethylfotmamide, is preferably used.

According to another feature of the present invention, the phenothiazine derivatives of general formula I wherein represents an alkanoyl radical containing 1 to 16 carbon atoms in the alkyl part or an alkenoyl radical containing 2 to 16 carbon atoms in the alkenyl part and R represents an alkyl radical containing 1 to 10 carbon atoms in the alkyl part, a phenylalkyl radical containing 1 to 4 carbon atoms in the alkyl part or a tetrahydropyranyl radical, the symbols X and A being as hereinbefore defined, are prepared by the process which comprises reacting a corresponding phenothiazine derivative of general formula I, wherein X, A and R are as just stated above and ^ represents a hydrogen atom, with a compound of the general formula: R3 - CO - Z XI wherein Rg represents an alkyl radical containing 1 to 16 carbon atoms or an alkenyl radical containing 2 to 16 carbon atoms, and Z represents a reactive radical such as a halogen atom, the hydroxy radical, a lower alkoxy radical containing 1 to 4 carbon atoms, an imidazolyl radical, or an alkanoyloxy or alkenoyloxy radical which can, in particular, be such that the compound Rg-CO-Z represents the acid anhydride of the formula R3 - CO - 0 - CO - R-,.

When the symbol Z represents a halogen atom, and in particular a chlorine atom, it is advantageous to carry out the reaction in an inert organic solvent, for example benzene, toluene or chloroform, at the boiling point of the solvent and in the presence or absence of an inorganic or organic basic acid-binding agent.

!Then the symbol Z represents the hydroxy radical, the reaction is generally carried out in an inert organic solvent, for example tetrahydrofuran, benzene, chloroform or dimethylformamide, in the presence either of a strong acid or a Lewis acid, or dicyclohexylcarbodiimide.

Mien the symbol Z represents a lower alkoxy radical, the reaction is generally carried out in an inert organic solvent, for example toluene, and the alcohol formed is removed by azeotropic distillation.

When the symbol Z represents an imidazolyl radical, the reaction is generally carried out in an inert organic solvent, for example benzene, tetrahydrofuran or chloroform, in the presence of sodium ethoxide at a temperature of about 20°C.

When the symbol Z represents an alkanoyloxy or alkenoyloxy radical, the reaction is carried out in the presence or absence of an inert organic solvent, for example chloroform, at a temperature between 50°C and the boiling point of the reaction mixture.

According to a still further feature of the present invention, the phenothiazine derivatives of general formula I, wherein R represents a hydrogen atom and the symbols X, A and R^ are as hereinbefore defined, are prepared from a corresponding phenothiazine derivative of general formula I, wherein X, A and R^ are as hereinbefore defined and R represents an alkyl radical containing 1 to 10 carbon atoms, a phenylalkyl radical containing 1 to 4 carbon atoms in the alkyl part, or a tetrahydropyranyl radical, in accordance with Imown methods for the replacement of an alkoxy, phenylalkoxy or tetra-hydropyranyloxy radical by a hydroxy radical without affecting the rest of the molecule. By the term "known methods" as used in this epecification is meant methods heretofore used or described in the chemical literature.

Generally the reaction is carried out in an acid medium in the presence of an organic solvent.

A phenothiazine derivative of general formula I v/herein R represents an isopropyl, benzyl or tetrahydropyranyl radical is preferably used, working in an organic solvent, e.g. chloroform, in the presence of sulphuric acid, and at a temperature between -10 and +10°C. 1*he phenothiazine derivatives of general formula I obtained by the aforementioned processes can optionally be purified by physical methods such as distillation, crystallisation or chromatography, or by chemical methods such as the formation of salts, crystallisation of the salts and decomposition of them in an alkaline medium. In carrying out the said chemical methods the nature of the anion of the salt is immaterial, the only requirement being that the salt must be well-defined and readily crystallisable.

The phenothiazine derivatives of general formula I can be converted by known methods into acid addition salts. The acid addition salts can be obtained by the action of acids on the phenothiazine bases in appropriate solvents. As organic solvents there may be used, for example, alcohols, ethers, ketones or chlorinated hydrocarbons. The salt which is formed is precipitated, if necessary after concentrating its solution, and is isolated by filtration or decantation.

The phenothiazine derivatives of general formula I and their acid addition salts possess useful pharmacodynamic properties: they are particularly active as anti-emetic agents.

The phenothiazine derivatives of general formula I wherein represents a hydrogen atom manifest powerful and specific anti-emetic activity, that is to say they are devoid of secondary central activity. In the dog, they have shown particularly valuable anti-emetic activity when administered orally or subcutaneously at doses of between 0.005 and 0.5 mg/kg. animal body weigh .

The phenothiaeine derivatives of general formula I v/herein represents an alkanoyl or alkenoyl radical have a long-lasting anti-emetic action. They have given good results in physiological ejcperiments on animals when administered subcutaneously or intramuscularly at doses of 0.010 to 2.0 mg/kg animal body weight.

The phenothiazine derivatives of general formula I v/herein R represents a hydrogen atom or an alkyl radical containing 1 to 7 carbon atoms, represents a hydrogen atom or an alkanoyl radical containing 1 to 6 carbon atoms in the alkyl part, or an alkenoyl radical containing 2 to 10 carbon atoms in the alkenyl part, X represents the dimethylsulp amoyl radical and ft represents -(CHj^-* are of particular interest. Examples of such compounds are 2-methoxy-6-dimethylsulphamoyl-10-[3- (4^nydroxyethyl-piperidino )propyl]phenothiazine, 2-isopropoxy-6-dimethylsulphamoyl-10- 3- (4-7 Shy2d-roxyethylpiperidino )-propyl]phenothiazine, 2-heptylo:cy-6-dimethylsulphamoyl-10- (2- [3-( ^hydro:∑yethylpiperidino )propyl]phenothiazine, 2-methoKy-6-dimethylsulphamoyl-10-[3-( neptanoyloxyethyl-piperidino )propyl]phenothiazine, 2-methoxy-6-dimeth l-sulphamoyl-10- 3-[4^iundec-10-enoyl )oxyethylpiperidino]-propyljphenothiazine, 2-metho:cy-6-di ethylsulphamoyl-10- /(2- [3-(4 acetoxyethylpiperidino )propyl]phenothiazine and (2 2-hydro5cy-6-dimethylsulphamoyl-10- [3-( -Viiydrojcyethyl-piperidino )propyl]phenothiazine.

For therapeutic purposes, the bases of general formula I are employed as such or in the form of nontoxic acid addition salts, e.g. salts containing anions which are relatively innocuous to the animal organism in therapeutic doses of the salts (such as hydrochlorides and other hydrohalides, phosphates, nitrates, sulphates, acetates, propionates, succinates, benzoates, fumarates, maleates, tartrates, methanesulphonates, ethanedisulphonate chlorotheophyllinates, theophylline-acetates, salicylates, phenolphthalinates, and methylene~bis-p-hydro:cnaphthoates) so that the beneficial physiological properties inherent in the bases are not vitiated by side-effects ascrxbable to the anions. - 11 - The following non-limitative Examples, and in which the numbering of the positions of the phenothiazine ring is that of Beilstein, illustrate the invention, BXftMPLS 1 A mixture of 2-methojcv--6-diniethylsulpharaoyl-10- (3-chloropropyl)phenothiazine (44.4 g. ) , 4-7h Sy2d-roxye hyl-piperidine (13.7 g. ) and sodium bicarbonate (35.8 Q". ) in diraeth lformamide (450 cc) is heated at about 130°C. for 7 hours with stirring. After cooling, the solution is evaporated to dryness under reduced pressure (15 mm.Hg) with heating to 6 °C. The crude product is taken up in distilled water (600 cc. ) and then extracted with methylene chloride (total 450 cc. j . The combined organic extracts are washed v.dth and then acidified by adding a solution of methanesulphonic acid (115.2 g. ) in water (600 cc.).

This acid solution is extracted with methylene chloride (total 600 cc.), She aqueous solution obtained is rendered allaline by adding a 15% solution of sodium hydroxide (colour change of phenolphthalein) and the base which precipitates is then extracted with methylene chloride ( total 500 cc. ) , The organic extract is washed with distilled water (total 600 cc.) and then dried over anhydrous sodium sulphate. The solvent is evaporated under reduced pressure (15 mm.Hg) at 40°C. Crude 2-methoxy-6-dimethyl- (2-suiphamoyl-10-[3-(4-hyd oxyethylpiperidino)propyljphenothi-azine (39.7 g. ) , in the form of a yellow amorphous powder is thus obtained.

A solution of tho crude base obtained above (39.4 g. ) in methylene chloride (300 cc.) is chromatographed on a column containing silica gel (400 g. ) (height : 500 mm., diameter : 45 mm. ) J elution is carried out using the ollov/ing solvents : methylene chloride 4 litres ethyl acetate 2 litres ethyl acetate/acetone (30/20 by volume) 2 litres ethyl acetate/acetone (50/50 by volume) 1 litre acetone 3 litres The way in which separation is progressing is followed by thin layer chromatography. The acetone eluate containing the purified base is concentrated to dryness under reduced pressure (15 rnm.Hg) , The purified base (27.6 g. ) is obtained in the form of a viscous oil.

The base thus obtained (14.9 g. ) is dissolved in boiling ethanol (50 cc. ) and then a boiling solution of oxalic acid (2,6 g, ) in ethanol (15 cc. ) is added. After cooling and the addition of isopropanol (25 cc. ) , crystallisation begins. The temperature is kept at about 5 °C. for 4 hours and then the crystals obtained are filtered off and washed successively with ethanol cooled to 5°G. (30 cc. ) and then with isopropanol cooled to 5°C. (75 cc.). 2\fter drying under reduced pressure (0.05 mm.Hg) for 16 hours at 5 °C, , 2-methoxy-6-dimethylsulphamoyl- (2-10- [3- ( -aydroxyethylpiperidino)propyl ]phenothiasine oxalate (15· g. ), melting at 174-176°C. , is obtained. 2-IIethoxy~6-dimethylsulphamoyl-10-( 3-chloro-propyDphenothiazine (m.p. 124-126°C. ; 62.6 g. ) is prepared by reacting l-bromo-3-chloropropane (147 g. ) with 2-raethoxy- 6-dimethy1sulphamoylphenothiamine (84,4 g, ) in the presence of powdered potassium hydroxide (25.8 g, ) in methyl ethyl ketone (300 cc.), 2-Methoxy-6-dimet ylsulphamoylpheno hiazine (m,p. .196-198°C, ; 79.6 g, ) is prepared by methylation, using dimethyl sulphate (74,5 g. ) , of 2-hydroxy-6-dimethylsulphamoylphenothiazine (168 g. ) in the presence of po/dered sodium hydroxide (30.8 g. ) suspended in methyl ethyl ketone (1,820 cc, ) . 2-Hydroxy-6-dimethy1sulphamo lphenothiasine (m.p. 208-210°C. ; 207,6 g. ) is prepared by reducing 6-di_nethy sulphamoylphenothiazin-2-one ( 250 g. ) by means of sodium hydrosulphite ( 190 g, ) in a mixture of methyl ethyl ketone (1,350 cc. ) and distilled water (450 cc.). 6-Dimethylsulphamoylphenothiazin-2-one (m.p. 244-245°C,; 320 g, ) is prepared by oxidising 3-dimethyl-sulphamoylphenothiazine (570 g. ) by means of a solution of ferric chloride (1,382 g. ) in distilled v/ater (2,000 cc.), dine (3.2 g. ) and sodium bicarbonate (8,4 g. ) in dimeth l ormamide (90 cc, ) is heated at 120°C, , with stirring, for 6 hours. The solvent is then evaporated under reduced pressure (0.1 mm.Hg) at 60°C. The residue is taken up in chloroform (80 cc, ) and distilled v/ater (80 cc. ) and purification of the product is effected by making the medium acidic and then reprecipitating the base by the procedure mentioned in Ξ:.ample 1. 2-Ilethoxy-6- (2-methylthio-10-[3-(4-hydroxye lpiperidino)propyl]-phenothiazine (7.9 g, ) in the crude state, in the form of an aiorphous beige powder, is thus obtained. This powder is taken up in boiling acetonitrile (15 cc.).

After cooling of the solution for 7 hours at a temperature of about 20°C, , the crystals which have formed are filtered off, washed with acetonitrile (10 cc. ) and with diethyl ether (60 cc. ) and then dried at 45°C. under reduced pressure (0.05 mrn.Hg)^ for 17 hours. 2-Methoxy-6-methylthio-10-[3-( -4iydroxyethylpiperidino)propyl]-phenothiazine (7.37 g. ) , melting at 101-103°C. , is obtained. 2-Iiethoxy-6-methylthio-10-( 3-chloropropyl )-phenothiazine (10,1 g. ) is prepared by reacting 1-bromo-3-chloropropane (47,5 g. ) with 2-methoxy-6-methyithio-phenothiazine (22.0 g, ) . 2- ethcxy-6-methylthiophenothiazine (m.p. 152-154°C; 20,1 g. ) is prepared by methylation of 2-hydroxy-6- ethylthiophenothiasine (37,8 g, ) by means of dimethyl sulphate (22,2 g. ) in the presence of sodium carbonate (30.1 g. ) in acetone. 2-Hydroxy-6-methylthiophenothiazine (m.p. 188-190 °C. 37.8 g. ) is prepared by reacting the zinc salt of 2-amino-4-methylthiothiophenol (45.0 g. ) with 2-chlorohydroquinone (m.p, 106-108°C. ; 64.0 g. ) in the presence of sodium hydroxide pellets (17.8 g. ) under a stream of oxygen, The phenothiazinone obtained is then reduced in situ by means of sodium hydrosulphite (81,0 g. ). 2-i¾mino-4-inethylthiothiophenol can be prepared in accordance with the method of Bourqu n et al, Helv* Chim. Acta, 42, 2546 (1959).

EXAMPLE.3 A mixture of 2-methoxy-6-methylsulphonyl-10-(3-chloropropyDphenothiazine (13,7 g. ) , 4-jfoydroxyethyl-piperidine (4,7 g, ) and sodium bicarbonate (12,0 g, ) in dimethylformamide (125 cc. ) is heated, with stirring, for 7 hours at 12 °C By following the procedure of Example 1 thereafter, a crude base (13,8 g, ) is obtained. This base dissolved in methylene chloride (150 cc,-) is chromatographed on a column (height : 450 mm, , diameter : 27 mm.) containing silica gel (130 g.), eluting with the following solvents: methylene chloride 300 cc, methylene chloride/ethyl acetate (50/50 by volume) 300 cc, ethyl acetate 900 cc, ethyl acetate/acetone (50/50 by volume) 300 cc, acetone 900 cc.

The way in which separation is progressing is followed by thin layer chromatography. The fractions corresponding to elution with pure ethyl acetate and with ethyl acetate/acetone are combined and the solvents are evaporated under reduced pressure (15 mm.Hg). The purified base (9,65 g, ) , in the form of a yellow-orange oil, is obtained.

This base is dissolved in anhydrous diethyl ether (185 cc,). After 24 hours at a temperature of about 20°C, followed by 7 hours at 5°C, , the crystals which have formed r are filtered off, washed with diethyl ether (total 200 ccj and dried at 45°C, under reduced pressure (0.01 mm.Hg) for 18 hours, 2-Methoxy-6-methylsulphonyl-10-[3-(4T4iydroxy-ethylpiperidino)propyl jphenothiazine (3.0 g, ) , melting at 117-118°C. , is obtained. 2-Methoxy-6-methylsulphonyl-10-(3-chloropropyl )-phenothiaaine (m.p. 122-12 °C. ; 15.0 g. ) is prepared by reacting l-bromo-3-chloropropane (30.4 g. ) with 2-methoxy-6-rnethylaulphonylphenothia2ine (15.9 g. ) in the presence of 8 % pure ground potassium hydroxide (5.6 g. ) dissolved in methyl ethyl ketone (75 cc,), 2-Methoxy-6-methylsulphonyIphenothiazine (m.p. 2-methoxy-6-rethylsuiphonyl' ^Tfflirophenothiasine 47 g. ) by means of zinc powder (28 g. ) in dimethylformamide (175 cc), acetic acid (73 cc. ) and distilled water (73 cc,). 2- ethoxy-6-methylsulphony1^9-oxophenothiazine -9-oxide (m.p. higher than 280 °C. ; 48 g. ) is prepared by oxidation of 2-methoxy-6-methylthio-10-acetylphenothiazine (m.p. 106-108°C,; 55.0 g. ) dissolved in 95% ethanol (95 cc. ) by means of 130 volumes hydrogen peroxide (S42 cc.}. The crude 2^methoxy-6-methylsulphonyl-Ρ-οκο-10-acetyIpheno- -9-oxide thiazino'' obtained (m.p. about 160°C, ) is saponified by means of an alcoholic solution of potassium hydroxide (11.2 g. ) in ethanol (200 cc.). 2-i'Iethoxy-6-methylthio-10-acetylphenothiazine (m.p. 106-108°C. ; 29.6 g. ) is prepared by acetylation of 2-methoxy-6-methylthiophenothiazine (m.p. 152-15 °C. ; 26.2 g. ) by means of acetic anhydride.

E AMPLE 4 A mixture of 2-isopropoxy-6-dimethylsulphamoyl-10-(3-chloropropyl)phenothiazine ( 27.8 g. ) , 4^hydroxyethyi-piperidina (8,2 g, ) and sodium bicarbonate (21,1 g, ) in dimethylformamide (265 cc.) is heated at 130°C. for 7 hours, The reaction mixture is then treated under the conditions mentioned in Example 1, The purified base (15 g, ) is thus obtained and, on lyophilisation of an aqueous solution of its hydrochloride, yields 2-isopropoxy-6-dimethy1suiphamoyl-10-[3-(4 hydroxye hylpiperidino )propyl]- henothiasine hydrochloride (11,6 g. ) melting at about 140°C.

Crude 2-isopropoxy-6-dim th 1 uiphamoyl-10-(3-chloropropyDphenothiasine (60 8 g, ) is prepared by reacting l-bromo-3-chloropropane (80,8 g. ) with 2-isopropoxy-6-dimethylsulphamoylphenothiazine (m.p. 187-189°C. ; 52.0 g. ) , 2-Isopropoxy-6-dimethylsulphamoylphenothiazine (42,3 g, ) is prepared by reacting 2-iodopropane (33,8 g. ) with 2-hydroxy-6-dimethylsulphamoylphenothiasine (40.0 g, ) prepared as indicated in Example 1, EXAMPLE 5 A mixture of 2-isopropoxy-6-methylsulphonyl-10-(3-chloropropyl)phenothiazine (20 g, ) , piperidine (6,4 g, ) and sodium bicarbonate (16,5 g, ) in dimethylformamide (170 cc, ) is heated at 150°C, for 7 hours 30 minutes with stirring. The reaction mixture is then treated under the conditions mentioned in Example 1, 2-Isopropoxy-6-methylsulphonyl-10-[3-(4Ahydroxy- ethylpiperidino)propyljphenothiazine (9.0 g. )f melting at about 50°C. , ia thue obtained.

Crude 2-isopropoxy-6-methylsulphonyl-10-( 3-chioropropyDphenotliazine (123 g. ) is prepared by reacting l-bromo-3-chloropropane (100 g. ) with 2-isopropoxy-6-methylsulphonylphenothiazine (m.p, 179-180°C. ; 100 g.). 2-Isopropoxy-6-met ylsulphonylphenothia2ine (21.7 g. ) is prepared by reacting 2-iodopropane (17.0 g. ) with 2-hydro y-6-methylsulphonylphenothiasine (m.p. 218-219 °C; 19.0 g. ) . 2-Hydroxy-6-methylsulphonylphenothiasine (126 g. ) is prepared by reduction of 6-raethylsulphonylphenothiazin-2-one (175 g. ) dissolved in methyl ethyl ketone (1,550 cc. ) by means of sodium hydrosulphite (152,5

Claims

VTE CLAIM

1. Phenothiazine derivatives of the general formula: wherein X represents a methylthio, methylsulphonyl or dimethylsulphamoyl radical, R represents a hydrogen atom or an alkyl radical containing 1 to 10 carbon atoms, a phenylalkyl radical containing 1 to 4 carbon atoms in the alkyl part, or a tetrahydropyranyl radical, A represents -(CH2)3- or -CI^-CKi CH3 )-CH2-, and represents a hydrogen atom or an alkanoyl radical containing 1 to 16 carbon atoms in the allcyl part or an alkenoyl radical containing 2 to 16 carbon atoms in the alkenyl part, and acid addition salts thereof.

2. Phenothiazine compounds according to claim 1 wherein R represents an alkyl radical containing 1 to 10 carbon atoms, R^ represents a hydrogen atom or an alkanoyl radical containing 4 to 16 carbon atoms in the allcyl part or an alkenoyl radical containing 4 to 16 carbon atoms in the alkenyl part, and X and A are as defined in claim 1.

3. Phenothiazine compounds according to claim 1 or 2 wherein A represents -(CE^^-.

4. Phenothiazine compounds according to claim 1 wherein R represents a hydrogen atom or an allcyl radical containing 1 to 7 carbon atoms, R^ represents a hydrogen atom or an alkanoyl radical containing 1 to 6 carbon atoms in the allcyl part or an alkenoyl radical containing 2 to 10 46484/2

5. 2-Methoxy-6-dimethylsulphamoyl-10-[3- (4- (2-hydroxyethyl) · piperidino) propyl) henothiazine and acid addition salts thereof.

6. 2-Isopropoxy-6-dimethyls lphamoyl-ie- [3- (4- (2-hydroxyethyl) piperidino)propyl]phenothiazine and acid addition salts thereof.

7. 2-Heptyloxy-6-dimethylsulphamoyl-10- [3- (4- (2-hydroxyethyl) piperidino) ropyl]-phenothiazine and acid addition salts thereof.

8. 2- ethoxy-6-dimethylsulphamoyl-10- [3- (4- (2-heptanoyloxyethyl) piperidino) propyl]phenothiazine and acid addition salts thereof.

9. 2-Methoxy-6-dimethylsulphamoyl-10-{3- [4- (2- (undec -10-enoyl)oxyethyl) piperidino]propyl}phenothiazine acid addition salts thereof.

10. 2-Methoxy-6-dimethylsulphamoyl-10- [3- (4- (2-acetoxyethyl) piperidino) propyl]phenothiazine and acid addition salts thereof.

11. 2-Hydroxy-6-dimethylsulphamoyl-10- [3- (4- (2-hydroxyethyl) piperidino) ropyl] henothiazine and acid addition salts thereof.

12. 2-Methoxy-6-methylthio-10- 13- (4- (2-hydroxyethyl) piperidino) and acid addition salts thereof.

13. 2-Methoxy-6-methylsulphonyl-10- [3- (4- (2-hydroxyethyl) piperidino)propyl]phenothiazine and acid addition salts thereof. - 36 - 46484/2

14. 2-Isopropoxy-6-methylsulphonyl-10- [3- (4- (2-hydroxyethyl)piperidino)propyl]phenothiazine and acid addition salts thereof.

15. 2-Benzyloxy-6-dimethylsulphamoyl-10- [3- (4- (2-hydroxyethy^piperidino) ropyl] -phenothiazine and acid addition salts thereof.

16. 2-Tetrahydropyranyloxy-6-dimethylsulphamoyl- 10- [3- (4- (2-hydroxyethyl) iperidino) propyl]phenothiazine and acid addition salts thereof.

17. 2-Methoxy-6-methylthio-10- [3- (4- (2-heptanoyloxyethyl) piperidino) propyl]phenothiazine and acid addition salts thereof.

18. 2-Methoxy-6-methylsulphonyl-10- [3- (4- (2-heptanoyl-oxyethyl) piperidino) propyl]phenothiazine and acid addition salts thereof.

19. 2-Benzyloxy-6-dimethylsulphamoyl-10- [3- (4- (2-acetoxyethyl) piperidino) ropyl]phenothiazine and acid addition salts thereof.

20. Process for the preparation of phenothiazine derivatives of the general formula depicted in claim 1, wherein R represents an alkyl radical containing 1 to 10 carbon atoms, a phenylalkyl radical containing 1 to 4 carbon atoms in the alkyl part, or a tetrahydropyranyl radical, R1 represents a hydrogen atom and the symbols X and A are as defined in claim 1, which comprises reacting a phenothiazine derivative of the general formula: A - Y (wherein X and A are as defined in claim 1, represents an alkyl radical containing 1 to 10 carbon atoms, a phenylalkyl radical containing 1 to 4 carbon atoms in the alkyl part, or a tetrahydropyranyl radical, and Y represents the acid residue of a reactive ester) with 4-(2-hydro:cyethyl )piperidine.

21. Process forthe preparation of phenothiazine derivatives of the general formula depicted in claim 1, wherein R^ represents an alkanoyl radical containing 1 to 16 carbon atoms in the alkyl part or an alkenoyl radical containing 2 to 16 carbon atoms in the alkenyl part, and R represents an alkyl radical containing 1 to 10 carbon atoms in the alkyl part, a phenylalkyl radical containing 1 to 4 carbon atoms in the alkyl part or a tetrahydropyranyl radical, the symbols X and A being as defined in claim 1, which comprises reacting a corresponding phenothiazine derivative of the general formula depicted in claim 1, wherein X, A and R are as just stated above and R^ represents a hydrogen atom, with a compound of the general formula: «3 - CO - Z wherein Rg represents an alkyl radical containing 1 to 16 carbon atoms or an alkenyl radical containing 2 to 16 carbon atoms, and 2 represents a reactive radical such as a halogen atom, the hydroxy radical, a lower alkojcy radical containing 1 to 4 carbon atoms, an imidazolyl radical, or an alkanoyl03cy or alkenoyloxy radical which can be such that the compound Rg-CO-Z represents the acid anhydride of the formula - CO - 0 - CO - Rg, the symbols Rg being

22. , Process for the preparation of phenothiazine derivatives of the general formula depicted in claim 1, wherein R represents a hydrogen atom and the symbols X* A and j^ are as defined in claim 1, which comprises treating a corresponding phenothiazine derivative of the general formula depicted in claim 1, wherein X, A and ^ are as defined in claim 1 and R represents an alkyl radical containing 1 to 10 carbon atoms, a phenylalkyl radical containing 1 to 4 carbon atoms in the alkyl part, or a tetrahydropyranyl radical, by known methods for the replacement of an alkoxy, phenylalkoxy or tetrahydropyranyloxy radical by a hydro2_y radical without affecting the rest of the molecule,

23. , Process according to claim 22 in which the phenothiazine starting material is treated with an acid medium in the presence of an organic solvent,

24. , Process according to claim 22 or 23 in which the phenothiazine starting material is a compound of the general formula depicted in claim 1 wherein R represents an isopropyl, benzyl or tetrahydropyranyl radical, and the phenothiazine derivative in an organic solvent is treated with sulphuric acid at a temperature between -10 and +10°C. to convert the R-Q- group in the 2-position of tho phenothiazine nucleus to the hydroxy radical,

25. , Process according to any one of claims 20 to 24 followed by the step of converting a phenothiazine product obtained into an acid addition salt. 39 -

26. Process for the preparation of phenothiazine derivatives of the general formula specified in claim 1 and acid addition salts thereof substantially as hereinbefore described with especial reference to any one of Examples 1 to 5 and 9 to 12.

27. Process for the preparation of phenothiazine derivatives of the general formula specified in claim 1 and acid addition salts thereof substantially as hereinbefore described with especial reference to any one of Examples 7, 8, 13, 14 and 15.

28. Process for the preparation of phenothiazine derivatives of the general formula specified in claim 1 and acid addition salts thereof substantially as hereinbefore described with especial reference to Example 6.

29. Phenothiazine derivatives of the general formula depicted in claim 1, and acid addition salts thereof, when prepared by a process claimed in any one of claims 20 to 2G.

30. Pharmaceutical compositions which comprise, as active ingredient, at least one phenothiazine derivative as claimed in any one of claims 1 to 19, or a non-toxic acid addition salt thereof, in association with a pharmaceutical carrier or coating.

31. Pharmaceutical compositions according to claim 30 substantially as hereinbefore described with especial reference to Example 16 or 17.